Unvetted drug indications mean safety uncertainties

The coincidence of two recent news items highlighted the tension between a more unfettered approach to pharmaceutical drug marketing and the need for caution when promoting and prescribing drugs.

A federal court judge issued a decision August 7 that ruled the drug company Amarin was not subject to Food and Drug Administration penalty for truthful but off-label promotion of the FDA-approved drug Vascepa, a triglyceride-lowering agent. Also on August 7, Dr. Frances Oldham Kelsey died at 101 years old. She was the FDA staffer singled out for recognition in 1962 as the primary firewall who prevented the agency from approving thalidomide for U.S. marketing as a treatment for morning sickness in pregnant woman, thereby sparing America from the epidemic of thalidomide-induced birth defects seen in Europe.

^{National LIbrary of Medicine http://www.nlm.nih.gov/changingthefaceofmedicine/physicians/biography_182.html}

Dr. Frances Oldham Kelsey received an award from President John F. Kennedy in 1962 for her role as an FDA staffer in blocking U.S. approval of thalidomide.

Despite the interesting juxtaposition of these two events, talking about them in the same breath requires a couple of important caveats: Vascepa has received FDA acceptance as safe for its approved indication, and circumstances would need to be unusual and severe for physicians to consider prescribing it to pregnant women. Society has dramatically changed the way it thinks about dosing pregnant women with drugs, compared with 60 years ago. It’s an attitudinal change driven at least in part by the thalidomide tragedy.

But the careful line that regulatory agencies and physicians must navigate that can mean denying patients potentially useful or even life-saving drugs because of insufficient evidence of safety and the need for caution against unsuspected consequences remains an enduring fact of medical practice.

Underappreciated threats exist even from drugs widely perceived as commonplace and benign. Consider NSAIDs. In July, the FDA strengthened and broadened its label warning for drugs in this class to say that treatment with NSAIDs of all types, including those sold OTC, can increase a person’s risk for MI, stroke, and heart failure, and that the elevated risk occurs even after just a few weeks of NSAID use.

Also in July, I covered a report at the Alzheimer’s Association International Conference 2015 on the off-label use for treating agitation in Alzheimer’s disease patients with the combination of dextromethorphan and quinidine, a formulation branded as Nuedexta with FDA approval for treating pseudobulbar affect. Although this combination is already on the U.S. market, and the main active agent dextromethorphan is also widely marketed in several OTC cough-medicine products, the principal investigator of the Alzheimer’s disease study, Dr. Jeffrey L. Cummings, told me that he cautions physicians against prescribing the dextromethorphan plus quinidine combination to patients with Alzheimer’s disease agitation, even though controlling Alzheimer’s agitation is a major unmet need for patients and their families. Dr. Cummings stressed that the 93 patients he studied during 10 weeks of treatment were too few people followed for too short a period to draw any conclusions on safety in this new patient population.

Once a drug receives FDA approval, and so presumably has an adequate evidence base proving clinical safety, extrapolation of its safety to different patient types can be tricky. As clinical experience with a drug or a drug class accumulates and as use expands to different sorts of patients, appreciation often grows for subtle or uncommon adverse effects not signaled during initial testing. How many physicians or patients suspected a potential risk from all prescription NSAIDs before the FDA issued its first warning about the class 10 year ago, and how many remained oblivious to the danger from OTC NSAIDs until the FDA strengthened its warning a few weeks ago? And nearly 60 years ago, few physicians aside from Dr. Kelsey and her associates at the FDA focused on the unanticipated danger posed by thalidomide treatment during pregnancy.

Truthful free speech about possible benefits of FDA-approved drugs for additional indications is a interesting concept, but physicians and patients must remain mindful of the need for caution and the danger of extrapolating too much and being too aggressive with drug use when an agent’s safety is uncertain.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler